PB1773: MYBLOCK: A MYELOID BLOOD CANCER INITIATIVE
Authors: L. Cairns, K. Clarke, M. Catherwood, K. Mills
Journal: HemaSphere (2022)

Background: MyBLOCk is a myeloid blood cancer initiative that encompasses a range of myeloid malignancies including Acute Myeloid Leukaemia (AML), Myelodysplastic Syndromes (MDS) and Myeloproliferative Neoplasms (MPN). These are a complex group of blood cancers that typically have poor overall survival. They result from genetic and epigenetic alterations that perturb key processes such as self- renewal, proliferation and differentiation. Despite improvements in overall survival, relapse rates in myeloid malignancies remain high. Standard of care therapies have not changed for many decades and often this intense chemotherapy is intolerable for older patients. Alongside this, there is an inherent complexity of these diseases. Over 70 different mutations have been identified in myeloid malignancies, patients typically display multiple mutations all of which contribute to the aggressiveness of the disease and the potential response to therapies. Aims: The overall aim of the MYBLOCk initiative is to adopt a personalised medicine approach for the treatment of myeloid malignancies. Using existing standard of care therapies alongside novel agents we aim to identify the most effective combination of compounds for an individual patient, at time of diagnosis. The ideal drug combination can then be mapped to the mutational spectrum of these patients to gain further insight into the clinical picture. Methods: We have created a custom panel of 48 compounds covering a range of different drug classes, many of which are already used in the treatment of myeloid malignancies. We want to investigate all possible pairwise combinations of these 48 compounds to determine the most effective combination for each patient, at diagnosis. Using a multiplex screening protocol that we have established in the lab, the compounds are grouped into pools of 5 compounds per well covering all potential pairs, this reduces the number of wells from 1128 to 172. Alongside this, a single agent screen of the 48 compounds is also performed. Peripheral blood mononuclear cells (PBMC) are added to the drug screen and incubated for 72 hours, the biological readout for this experiment is CellTox™ Green Express Cytotoxicity Assay. Results: For each of the 172 5-compound combinations a Z-Score is calculated based on normalised relative fluorescence values. Combinations with a Z-Score>2 are taken forward for further investigation. A 5-compound combination is then deconvoluted into 10 pairwise combinations and 10 triple combinations, to identify a more clinically feasible combination for each patient. Alongside this screening strategy, each patient has undergone RNA sequencing at diagnosis to determine their mutational spectrum. By comparing the mutational landscape of each patient to their response to the MYBLOCk screening protocol we can investigate the relationship between molecular data and sensitivity to combination therapy. Multiple myeloid patient samples have been examined using this approach and have demonstrated a potential therapeutic backbone. Triple combinations involving a backbone of idarubicin and pracinostat with the addition of patient specific third agent has shown sensitivity. Summary/Conclusion: Moving forward with the MYBLOCk initiative we will build a database of mutational information alongside sensitivity to the MYBLOCk panel to allow the rapid identification of personalised therapeutic options highlighting more effective, and novel, combinations for a wider range of patients at diagnosis.